Macrolide antibiotics play an important role clinically as they have good activity against gram-positive bacteria, and some gram-negative bacteria as well and have good antibacterial activity and tissue permeability for uncontrollable causative agents such as some increasingly epidemic toxoplasm and legionella. Featured by fast absorption by oral administration, few adverse reactions, macrolide antibiotics basically have no effect on the liver and kidney but have potential immunoregulation function. In the nineties, macrolide antibiotics were thought to be a competitor for β-lactam drugs in treating respiratory tract infection of adults.
Chirality is a basic attribute of three-dimensional body and one of the essential attributes of nature. Biological macromolecules including protein, polysaccharide, nucleic acid and enzyme as important basis of vital movement often have important physiological functions. Chiral drug is a pair of enantiomers of material object and mirror image obtained after molecular structure of drug is introduced into the chiral center. These enantiomers are basically the same regarding physicochemical properties but different in optical activity. The enantiomers are respectively named R-type (dextrorotatory) or S-type (sinistral), and racemic. In recent 20 years, as pharmaceutical research is more intensive, it has been proved that the difference of drug enantiomer's affinity with receptor caused by the difference of drug enantiomer's stereoselectivity leads to great difference in pharmacological action. Enantiomer with high activity among chiral drugs is called eutomer; while the one with low or no activity is called distomer. In many cases, the distomer not only has no pharmacological action, but also offset that of eutomer. Sometimes, severe toxic side reactions will occur, showing the complexity of difference in pharmacological function and determining great difference in the therapeutic index of single enantiomer and the racemate thereof. For example, the curative effect of well-known DL-(+−) syntomycin is half of D(−) chloramphenicol; the pharmaceutical activity of propranolol L-isomer is 100 times larger than that of D-isomer; (−) adanon is a strong painkiller while (+) is non-effective. There is also difference in toxicity. For example, the two enantiomers of thalidomide have similar sedation for mice, but only S(−) isomer and metabolin thereof have embryotoxin and teratogenesis; ketamine is a widely used anaesthetic and analgesic, but has side effects such as hallucinating. Studies show that S (+) is 3˜4 times more effective than R(−) and toxic side effects have something to do with the latter. The great difference of chiral drug's curative effect has promoted the research and development of chiral drugs and the development separation analysis. By using “chiral” technology, we can remove those with no effect or toxic side effects from drugs effectively and produce pure chiral drugs with single and oriented structure, thus making more pure pharmaceutical ingredients, further quickening curative effect and shortening the course of treatment. Therefore, research on chiral drugs has become one of the new methods for new medicine research worldwide. National governments and pharmaceutical enterprises have invested heavily in fields such as preparations of chiral drug, chiral materials and chiral intermediate for research and development, for the purpose of seizing dominance of chiral pharmacy market. Besides, with continuous improvement of chiral technology, especially the fast and wide use of liquid chromatography, the separation analysis and determination of enantiomers of chiral drugs are promoted. Chiral drugs of single enantiomer have been widely used.
Carrimycin is a new derivative of spiramycin developed by adopting genetic engineering technology, which is originally named biotechspiramycin and formerly named biotechmycin [Patent No.: ZL97104440.6]. According to the “Rules for Chinese Approved Drug Names”, and upon technical review and confirmation of Chinese Pharmacopoeia Commission, the generic name of biotechspiramycin is changed to carrimycin. The chemical structure of carrimycin mainly comprises 4″-isovalerylspiramycin, including 4″-isovalerylspiramycin I, II, III, and about 6 4″-hydroxy acylated spiramycin, so the chemical name is 4″-acylspiramycin.
Chemical structural formula of carrimycin is as shown in formula (1):

Wherein: R in isovalerylspiramycin I is from H;
R in isovalerylspiramycin II is from COCH3, R in isovalerylspiramycin III is from COCH2CH3.
Carrimycin is a 16-membered ring macrolide antibiotic, which inhibits the protein synthesis by combining with ribosome of bacterium.
Pharmacokinetics study shows that effective components of carrimycin with activity are mainly isovalerylspiramycin I, II and III. Carrimycin quickly metabolizes to spiramycin in vivo. According to AUC0-t of parent drug isovalerylspiramycin I, II and II and active metabolite spiramycin I, II and III, the absolute bioavailability by oral administration is 91.6% averagely. It is reported that the absolute bioavailability of spiramycin by oral administration is 30˜40% (Frydman A M et al J Antimicrob Chemother. 1988, 22(suppl B):93-103). It shows that the isovalerylspiramycin apparently improves the bioavailability of active component spiramycin. Single dose carrimycin is eliminated slowly. T1/2 is between 23˜27 hours.
In vitro test results show that carrimycin is effective against gram-positive bacteria, especially some drug-resistance bacteria such as β-lactam resistance staphylococcus aureus and erythrocin-resistance staphylococcus aureus, and has no apparent cross resistance with similar drugs. Meanwhile, carrimycin has antibacterial activity for mycoplasma and chlamydia, as well as some gram-negative bacteria, has good antibacterial activity and tissue permeability for epidemic toxoplasm and legionella, and still has potential immunoregulation function. The antibacterial activity in vivo is much better than that in vitro (ZL200310122420.9). Clinical research shows that by taking carrimycin tablets 200 mg˜400 mg everyday for 5˜7 days, it is suitable for treating acute bacterial pharyngitis and acute suppurative tonsillitis caused by pyogenic streptococcus; bacterial nasosinusitis and acute bronchitis caused by sensitized bacteria; mild pneumonia caused by streptococcus pneumonia, haemophilus influenza and mycoplasma pneumonia; nongonoccal urethritis caused by mycoplasma and chlamydia; infectious diseases such as skin and soft tissue infection, periodontitis and otitis media caused by sensitized bacteria. The total effective rate is 92.68%.
Clinical research proves that carrimycin is an antibiotic safe and effective by oral administration. However, as carrimycin is a product obtained through fermentation and is a multicomponent drug, it is very difficult to further separate and purify multicomponent drugs. The current HPLC can separate the multiple acylspirmycins in carrimycin sample, for example, the separation degree of isovalerylspiramycin II and isobutyrylspiramycin III, isobutyrylspiramycin II and propionylspiramycin III, propionylspiramycin III and said component, propionylspiramycin II and acetyl spiramycin III is higher than 1.5 as stipulated in Chinese Pharmacopoeia, while that of acetyl spiramycin III and said component is 1.2.
Through lots of researches and adjustment and optimization of culturing and fermentation conditions, the inventor gets a levocarrimycin, which has better anti-infection activity.
At present, HPLC is employed and it is determined that carrimycin comprises 9 acylspiramycin components, including isovalerylspiramycin (I+II+III), which should not be less than 60% in total, and acylspiramycin, which should not be less than 80% in total. It is quite hard to meet the quality control standard of injection for multicomponent antibiotics produced through fermentation, but injection takes effect quickly for critical patients and those who should not take medicine orally, thus single-component preparation of isovalerylspiramycin is of profound significance. In the present invention, through further research on levocarrimycin, single component of levoisovalerylspiramycin I with purity as high as 98 wt % is obtained.